The show starred Don Johnson as an Inspector (later Captain in season 4) with the San Francisco Police Department's elite "Special Investigations Unit". As the show begins, he's in his 40s, twice-divorced, and dealing with a feisty teenage daughter, Cassidy (played by Jodi Lyn O'Keefe). Nash convinces recently retired Inspector Joe Dominguez (played by Cheech Marin) to return to the force to partner with him. Nash and Joe cruise the streets of San Francisco in Nash's "curious yellow" 1971 Plymouth Barracuda convertible, a gift from Nash's brother Bobby just before Bobby left for the Vietnam War. Bobby Bridges was reported as MIA, but turns up in later seasons. Nash's father Nick (played by James Gammon) suffers from mild dementia and has a habit of getting kicked out of nursing homes. He eventually moves in with Nash, and is often involved in comic subplots.

Aiding Nash in his police work is the technically savvy Harvey Leek (played by Jeff Perry), a middle-aged "Deadhead" (a die-hard Grateful Dead fan), and young, hotheaded Evan Cortez (played by Jaime P. Gomez, 1996–2000), who has an off-and-on, stormy relationship with Cassidy. In later seasons, additional Inspectors and other supporting characters were added and subtracted from the main cast. For the first nine episodes, the commander of the SIU was Lieutenant A.J. Shimamura (played by Cary-Hiroyuki Tagawa in season 1-2 only), a character that was written off after he failed to be promoted to Captain. (The character was said to have returned to his native Hawaii.) Shimamura's departure opened the door for Bridges to be promoted to Captain, and given command of the SIU.